Vision through photodynamic therapy of the eye

ABSTRACT

Photodynamic therapy of conditions of the eye, especially those conditions characterized by unwanted neovasculature, such as age-related macular degeneration, results in enhanced visual acuity for treated subjects.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.11/852,965, filed Sep. 10, 2007, which is a continuation of U.S.application Ser. No. 10/383,820, filed Mar. 7, 2003, which is acontinuation of U.S. application Ser. No. 09/300,979, filed Apr. 28,1999, now U.S. Pat. No. 6,548,542, which is a continuation of U.S.application Ser. No. 09/083,480, filed May 22, 1998, now U.S. Pat. No.5,910,510, which is a continuation of U.S. application Ser. No.08/613,420, filed Mar. 11, 1996, now U.S. Pat. No. 5,756,541. Thedisclosures of which are herein incorporated by reference in theirentirety.

TECHNICAL FIELD

The invention relates to a method to improve visual acuity byadministering photodynamic therapy (PDT) to the eye.

BACKGROUND ART

Loss of visual acuity is a common problem associated with aging and withvarious conditions of the eye. Particularly troublesome is thedevelopment of unwanted neovascularization in the cornea, retina orchoroid. Choroidal neovascularization leads to hemorrhage and fibrosis,with resultant visual loss in a number of recognized eye diseases,including macular degeneration, ocular histoplasmosis syndrome, myopia,and inflammatory diseases. Age-related macular degeneration (AMD) is theleading cause of new blindness in the elderly, and choroidalneovascularization is responsible for 80% of the severe visual loss inpatients with this disease. Although the natural history of the diseaseis eventual quiescence and regression of the neovascularization process,this usually occurs at the cost of sub-retinal fibrosis and vision loss.

Current treatment of AMD relies on occlusion of the blood vessels usinglaser photocoagulation. However, such treatment requires thermaldestruction of the neovascular tissue, and is accompanied byfull-thickness retinal damage, as well as damage to medium and largechoroidal vessels. Further, the subject is left with an atrophic scarand visual scotoma. Moreover, recurrences are common, and visualprognosis is poor.

Developing strategies have sought more selective closure of the bloodvessels to preserve the overlying neurosensory retina. One such strategyis photodynamic therapy, which relies on low intensity light exposure ofphotosensitized tissues to produce deleterious effects. Photoactivecompounds are administered and allowed to reach a particular undesiredtissue which is then irradiated with a light absorbed by the photoactivecompound. This results in destruction or impairment of the surroundingtissue.

Photodynamic therapy of conditions in the eye has been attempted overthe past several decades using various photoactive compounds, e.g.,porphyrin derivatives, such as hematoporphyrin derivative and Photofrinporfimer sodium; “green porphyrins”, such as benzoporphyrin derivative(BPD), MA; and phthalocyanines. Schmidt, U. et al. described experimentsusing BPD coupled with low density lipoprotein (LDL) for the treatmentof Greene melanoma (a nonpigmented tumor) implanted into rabbit eyes andachieved necrosis in this context (IOVS (1992) 33:1253 Abstract 2802).This abstract also describes the success of LDL-BPD in achievingthrombosis in a corneal neovascularization model. The corneal tissue isdistinct from that of the retina and choroid.

Treatment of choroidal neovascularization using LDL-BPD or liposomal BPDhas been reported in IOVS (1993) 34:1303: Schmidt-Erfurth, U. et al.(abstract 2956); Haimovici, R. et al. (abstract 2955); Walsh, A. W. etal. (abstract 2954). Lin, S. C. et al. (abstract 2953). An additionalpublication is Moulton, R. S. et al. (abstract 2294), IOVS (1993)34:1169.

It has now been found that photodynamic treatment of eye conditionsunexpectedly enhances the visual acuity of the subject.

DISCLOSURE OF THE INVENTION

The invention is directed to a method to improve visual acuity usingphotodynamic treatment methods. The methods are particularly effectivewhen the photodynamic therapeutic protocol results in a diminution ofunwanted neovasculature, especially neovasculature of the choroid.

Accordingly, in one aspect, the invention is directed to a method toenhance visual acuity which comprises administering to a subject in needof such treatment an amount of a formulation of a photoactive compoundsufficient to permit an effective amount to localize in the eye of saidsubject; permitting sufficient time to elapse to allow an effectiveamount of said photoactive compound to localize in said eye; andirradiating the eye with light absorbed by the photoactive compound

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1F show preferred forms of the green porphyrins useful in themethods of the invention.

FIG. 2 shows the visual acuity response of individual patients subjectedto PDT over time.

FIG. 3 shows the effect of repeated PDT in individual patients onmaintaining enhanced visual acuity.

MODES OF CARRYING OUT THE INVENTION

In the general approach that forms the subject matter of the invention,a human subject whose visual acuity is in need of improvement isadministered a suitable photoactive compound in amount sufficient toprovide an effective concentration of the photoactive compound in theeye. After a suitable time period to permit an effective concentrationof the compound to accumulate in the desired region of the eye, thisregion is irradiated with light absorbed by the photoactive compound.The irradiation results in excitation of the compound which, in turn,effects deleterious effects on the immediately surrounding tissue. Theultimate result is an enhancement of visual acuity in the subject.

Photoactive Compounds

The photodynamic therapy according to the invention can be performedusing any of a number of photoactive compounds. For example, variousderivatives of hematoporphyrin have been described, includingimprovements on hematoporphyrin derivative per se such as thosedescribed in U.S. Pat. Nos. 5,028,621; 4,866,168; 4,649,151; and5,438,071, the entire contents of which are incorporated herein byreference. In addition, pheophorbides are described in U.S. Pat. Nos.5,198,460; 5,002,962; and 5,093,349; bacteriochlorins in U.S. Pat. Nos.5,171,741 and 5,173,504; dimers and trimers of hematoporphyrins in U.S.Pat. Nos. 4,968,715 and 5,190,966. The contents of these patents arealso incorporated herein by reference. In addition, U.S. Pat. No.5,079,262 describes the use of a precursor to hematoporphyrin,aminolevulinic acid (ALA), as the source of a photoactive compound. Theuse of phthalocyanine photosensitizers in photodynamic therapy isdescribed in U.S. Pat. No. 5,166,197. The contents of all of theforegoing patents are incorporated herein by reference. Other possiblephotoactive compounds include purpurins, merocyanines and porphycenes.Particular preferred photoactive compounds for use in the inventionmethod are the green porphyrins. These porphyrins are described in U.S.Pat. Nos. 4,883,790; 4,920,143; 5,095,030; and 5,171,749, the entirecontents of which are incorporated herein by reference. As thesephotoactive agents represent a particularly preferred embodiment,typical formulas for these compounds are represented herein in FIG. 1.

Referring to FIG. 1, in preferred embodiments each of R¹ and R² isindependently selected from the group consisting of carbalkoxyl (2-6C),alkyl (1-6C), arylsulfonyl (6-10C), cyano and —CONR⁵CO wherein R⁵ isaryl (6-10C) or alkyl (1-6C); each R³ is independently carboxyl,carboxyalkyl (2-6C) or a salt, amide, ester or acylhydrazone thereof oris alkyl (1-6C); R⁴ is CH═CH₂ or —CH(OR^(4′))CH3 wherein R^(4′) is H, oralkyl (1-6C) optionally substituted with a hydrophilic substituent.Especially preferred also are green porphyrins of the formula shown inFIG. 1C or 1D or mixtures thereof.

More preferred are embodiments are those wherein the green porphyrin isof the formula shown in FIG. 1C or 1D or a mixture thereof and whereineach of R¹ and R² is independently carbalkoxyl (2-6C); one R³ iscarboxyalkyl (2-6C) and the other R³ is an ester of a carboxyalkyl(2-6C) substituent; and R⁴ is CH═CH₂ or —CH(OH)CH₃.

Still more preferred are embodiments wherein green porphyrin is of theformula shown in FIG. 1C and wherein R¹ and R² are methoxycarbonyl; oneR³ is —CH₂CH₂COOCH₃ and the other R³ is CH₂CH₂COOH; and R⁴ is CH═CH₂;i.e., BPD-MA.

Any of the photoactive compounds described above can be used in themethod of the invention; of course, mixtures of two or more photoactivecompounds can also be used; however, the effectiveness of the treatmentdepends on the absorption of light by the photoactive compound so thatif mixtures are used, components with similar absorption maxima arepreferred.

Formulations

The photoactive agent is formulated so as to provide an effectiveconcentration to the target ocular tissue. The photoactive agent may becoupled to a specific binding ligand which may bind to a specificsurface component of the target ocular tissue or, if desired, byformulation with a carrier that delivers higher concentrations to thetarget tissue.

The nature of the formulation will depend in part on the mode ofadministration and on the nature of the photoactive agent selected. Anypharmaceutically acceptable excipient, or combination thereof,appropriate to the particular photoactive compound may be used. Thus,the photoactive compound may be administered as an aqueous composition,as a transmucosal or transdermal composition, or in an oral formulation.The formulation may also include liposomes. Liposomal compositions areparticularly preferred especially where the photoactive agent is a greenporphyrin. Liposomal formulations are believed to deliver the greenporphyrin selectively to the low-density lipoprotein component of plasmawhich, in turn acts as a carrier to deliver the active ingredient moreeffectively to the desired site. Increased numbers of LDL receptors havebeen shown to be associated with neovascularization, and by increasingthe partitioning of the green porphyrin into the lipoprotein phase ofthe blood, it appears to be delivered more efficiently toneovasculature.

As previously mentioned, the method of the invention is particularlyeffective where the loss of visual acuity in the patient is associatedwith unwanted neovasculature. Green porphyrins, and in particularBPD-MA, strongly interact with such lipoproteins. LDL itself can be usedas a carrier, but LDL is considerably more expensive and less practicalthan a liposomal formulation. LDL, or preferably liposomes, are thuspreferred carriers for the green porphyrins since green porphyrinsstrongly interact with lipoproteins and are easily packaged inliposomes. Compositions of green porphyrins involving lipocomplexes,including liposomes, are described in U.S. Pat. No. 5,214,036 and inU.S. Ser. No. 07/832,542 filed 5 Feb. 1992, the disclosures of both ofthese being incorporated herein by reference. Liposomal BPD-MA forintravenous administration can also be obtained from QLTPhotoTherapeutics Inc., Vancouver, British Columbia.

Administration and Dosage

The photoactive compound can be administered in any of a wide variety ofways, for example, orally, parenterally, or rectally, or the compoundmay be placed directly in the eye. Parenteral administration, such asintravenous, intramuscular, or subcutaneous, is preferred. Intravenousinjection is especially preferred.

The dose of photoactive compound can vary widely depending on the modeof administration; the formulation in which it is carried, such as inthe form of liposomes; or whether it is coupled to a target-specificligand, such as an antibody or an immunologically active fragment. As isgenerally recognized, there is a nexus between the type of photoactiveagent, the formulation, the mode of administration, and the dosagelevel. Adjustment of these parameters to fit a particular combination ispossible.

While various photoactive compounds require different dosage ranges, ifgreen porphyrins are used, a typical dosage is of the range of 0.1-50mg/m² (of body surface area) preferably from about 1-10 mg/m² and evenmore preferably about 2-8 mg/m².

The various parameters used for effective, selective photodynamictherapy in the invention are interrelated. Therefore, the dose shouldalso be adjusted with respect to other parameters, for example, fluence,irradiance, duration of the light used in photodynamic therapy, and timeinterval between administration of the dose and the therapeuticirradiation. All of these parameters should be adjusted to producesignificant enhancement of visual acuity without significant damage tothe eye tissue.

Stated in alternative terms, as the photoactive compound dose isreduced, the fluence required to close choroidal neovascular tissuetends to increase.

Light Treatment

After the photoactive compound has been administered, the target oculartissue is irradiated at the wavelength absorbed by the agent selected.The spectra for the photoactive compounds described above are known inthe art; for any particular photoactive compound, it is a trivial matterto ascertain the spectrum. For green porphyrins, however, the desiredwavelength range is generally between about 550 and 695 nm. A wavelengthin this range is especially preferred for enhanced penetration intobodily tissues.

As a result of being irradiated, the photoactive compound in its excitedstate is thought to interact with other compounds to form reactiveintermediates, such as singlet oxygen, which can cause disruption ofcellular structures. Possible cellular targets include the cellmembrane, mitochondria, lysosomal membranes, and the nucleus. Evidencefrom tumor and neovascular models indicates that occlusion of thevasculature is a major mechanism of photodynamic therapy, which occursby damage to endothelial cells, with subsequent platelet adhesion,degranulation, and thrombus formation.

The fluence during the irradiating treatment can vary widely, dependingon type of tissue, depth of target tissue, and the amount of overlyingfluid or blood, but preferably varies from about 50-200 Joules/cm².

The irradiance typically varies from about 150-900 mW/cm², with therange between about 150-600 mW/cm² being preferred. However, the use ofhigher irradiances may be selected as effective and having the advantageof shortening treatment times.

The optimum time following photoactive agent administration until lighttreatment can also vary widely depending on the mode of administration,the form of administration and the specific ocular tissue beingtargeted. Typical times after administration of the photoactive agentrange from about 1 minute to about 2 hours, preferably bout 5-30minutes, and more preferably 10-25 minutes.

The duration of light irradiation depends on the fluence desired; for anirradiance of 600 mW/cm² a fluence of 50 J/cm² requires 90 seconds ofirradiation; 150 J/cm² requires 270 seconds of irradiation.

Evaluation of Treatment

Clinical examination and fundus photography typically reveal no colorchange immediately following photodynamic therapy, although a mildretinal whitening occurs in some cases after about 24 hours. Closure ofchoroidal neovascularization is preferably confirmed histologically bythe observation of damage to endothelial cells. Observations to detectvacuolated cytoplasm and abnormal nuclei associated with disruption ofneovascular tissue may also be evaluated.

In general, effects of the photodynamic therapy as regards reduction ofneovascularization can be performed using standard fluoresceinangiographic techniques at specified periods after treatment.

Of paramount importance with respect to the present invention is theevaluation of visual acuity. This is done using means standard in theart and conventional “eye charts” in which visual acuity is evaluated bythe ability to discern letters of a certain size, usually with fiveletters on a line of given size. Measures of visual acuity are known inthe art and standard means are used to evaluate visual acuity accordingto the present invention.

The following examples are to illustrate but not to limit the invention.

Example 1 Comparison of Various PDT Regimens

Groups of patients who had been diagnosed as qualified for experimentaltreatment of age-related macular degeneration (AMD) were divided intothree groups.

Group A, of 22 patients, was treated with a regimen in which they wereadministered 6 mg/m² (of body surface area) of BPD-MA in thecommercially available liposomal intravenous composition obtainable fromQLT PhotoTherapeutics, Vancouver, BC. Administration was intravenous.Thirty minutes after the start of infusion, these patients wereadministered irradiance of 600 mW/cm² and total fluence of either 50J/cm², 75 J/cm², 100 J/cm², 105 J/cm² or 150 J/cm² of light from acoherent Argon dye laser No. 920, Coherent Medical Laser, Palo Alto,Calif. (Ohkuma, H. et al. Arch Ophthalmol (1983) 101:1102-1110; Ryan, S.J., Arch Ophthalmol (1982) 100:1804-1809).

A second group of 15 patients, Group B, was also administered 6 mg/m²BPD-MA in the liposomal formulation, intravenously as in Group A, butirradiation, conducted as described for Group A, began 20 minutes afterthe start of infusion.

The 15 patients in Group C were subjected to a regime identical to thosein Group A except that the BPD-MA was administered at 12 mg/m²

To evaluate the patients after treatment, fluorescein angiography wasperformed 1 week, 4 weeks and 12 weeks after treatment. Visual acuitytests using standard eye charts were administered 3 months aftertreatment. The change in visual acuity was averaged for each groupregardless of the total fluence of light administered.

After 3 months, patients subjected to regimen A showed an improvement invisual acuity of +0.10 (an improvement of 1.0 would indicate animprovement of one line on the conventional eye charts). Patientssubjected to regimen B showed an enhancement of visual acuity of +0.53;those on regimen C decreased in visual acuity at an average of −0.40.

By comparison, 184 patients treated using standard photocoagulationtreatment as described by a Macular Photocoagulation Study Group inClinical Sciences (1991) 109:1220-1231, showed a diminution in visualacuity 3 months after treatment of −3.0. This was worse than the resultsof no treatment where a sample of 179 patients suffering from AMD showeda loss of visual acuity over this time period of −2.0.

Thus, it appeared that regimen B wherein 6 mg/m² of BPD in a liposomalformulation were administered and irradiation began 20 minutes later wasthe best of these three protocols tested.

Example 2 Time Course of Enhancement of Visual Acuity

Sixteen patients in the study were subjected to regimen B described inExample 1 above and evaluated for visual acuity after 1 week and after 4weeks as well as after 3 months. One week after treatment these patientshad an average increase in visual acuity of +2.13; 4 weeks aftertreatment the average was +1.25 and after 3 months, +0.53.

These results seemed at least partly to correlate with success inclosing choroidal neovasculature (CNV). For those patients in regimen B,10 of the 16 tested by fluorescein angiography showed CNV more than 50%closed after 4 weeks with a corresponding increase in visual acuity of+1.6. The remaining 6 patients who showed less than 50% closure of CNVafter 4 weeks showed an enhanced visual acuity of +0.7.

Of 15 patients subjected to regimen C of Example 1, 7 showed more than50% closure of CNV and an enhanced visual acuity of +1.4. Three of the15 showed less than 50% closure of CNV and showed a loss of visualacuity of −0.3. Five of the 15 showed classic CNV recurrence and showeda loss of visual acuity of −1.6.

On the other hand, after 4 weeks of treatment with regimen A, 9 of 21patients showed a CNV of more than 50% closure but a decline in visualacuity of −0.2. Nine of the 21 showed a closure of CNV of less than 50%and an enhanced visual acuity of +0.9. Three of the 21 patients treatedwho showed classic CNV recurrence showed no change in visual acuity.

After 3 months, the results are as shown in Table 1, where the change invisual acuity observed is noted.

TABLE 1 Regimen A Regimen B Regimen C Classic CNV ≧50% closed +0.7 +3 —(3/20) (4/13) (0/12) Classic CNV <50% closed  +0.14 0 +1.75 (7/20)(3/13) (4/12) Classic CNV Recurrence −0.1 −0.3 −1.4  (10/20) (6/13)(8/12)

Thus, there appears to be some, but far from perfect correlation betweenCNV closure and enhancement of visual acuity. The method of theinvention may thus be most readily applied to patients showing unwantedneovasculature, especially in the choroid. Thus, suitable indicationswould include macular degeneration, ocular histoplasmosis syndrome,myopia, and inflammatory diseases.

FIG. 2 shows a graphic representation of the time course of change invisual acuity of individual patients subjected to regimen B. Allpatients showed improvement, although in some cases the improvementdiminished over time after treatment.

Example 3 Effect of Iterative Treatment

Individual patients were treated with regimen B as described in Example1 and then retreated at 2 and 6 weeks from the initial treatment.Repeating the treatment appeared to enhance the degree of increasedvisual acuity. The results are summarized in FIG. 3.

As shown in FIG. 3, for example, patient no. 901 starting at a base lineof 20/126 showed an enhancement of +2 in visual acuity after week 2; twoweeks after a second treatment, the enhancement was +5 over base line.For patient 906, the enhancement after the first treatment at week 2 was+2; this increased to +3 one week after a second treatment. While somepatients showed slight relapses, in general, repeating the regimenmaintained or increased enhancement of visual acuity.

1. An aqueous composition comprising a green porphyrin and a low-densitylipoprotein component of plasma.
 2. A method of delivering a greenporphyrin to a site of neovasculature in a human subject, said methodcomprising use of a low-density lipoprotein component of plasmacomprising a green porphyrin.
 3. A method of treating choroidalneovasculature in a human subject, which method comprises: irradiatingsaid subject's ocular tissue containing said neovasculature with lightabsorbed by a photoactive compound, and repeating said irradiating ofocular tissue at least once, wherein said subject has been administeredthe photoactive compound before each irradiating of ocular tissue;wherein the wavelength of the light is absorbed by the photoactivecompound; and wherein said irradiation is conducted for a time and at anintensity sufficient to treat said choroidal neovasculature.
 4. Themethod of claim 3 wherein the photoactive compound is a green porphyrin,a hematoporphyrin derivative, a chlorin, or a phlorin.
 5. The method ofclaim 4 wherein said green porphyrin is of the formula

wherein each of R¹ and R² is independently selected from the groupconsisting of carbalkoxyl (2-6C), alkyl (1-6C), arylsulfonyl (6-10C),cyano and —CONR⁵CO— wherein R⁵ is aryl (6-10C) or alkyl (1-6C); each R³is independently carboxyl, carboxyalkyl (2-6C) or a salt, amide, esteror acyl hydrazone thereof, or is alkyl (1-6C); R⁴ is CH═CH₂ or—CH(OR^(4′))CH₃ wherein R^(4′) is H, or alkyl (1-6C) optionallysubstituted with a hydrophilic substituent.
 6. The method of claim 3wherein said irradiation is administered at an irradiance of about 600mW/cm² to provide a total fluence of 50 J/cm²-150 J/cm² of said light.7. The method of claim 3 wherein said repeating is at two weeksfollowing an initial irradiating of ocular tissue.
 8. The method ofclaim 3 wherein said repeating is at six weeks following an initialirradiating of ocular tissue.
 9. The method of claim 3 wherein saidsubject has been diagnosed with age-related macular degeneration (AMD).10. The method of claim 3 wherein the subject has been diagnosed with acondition selected from the group consisting of macular degeneration,ocular histoplasmosis syndrome, myopia, and inflammatory diseases.